Lipophilic quaternary ammonium salicylates, their use in cosmetics and in dermopharmacy

ABSTRACT

Lipophilic quaternary ammonium salicylate, characterized in that it corresponds to the formula:  &lt;IMAGE&gt;  in which: (i) R1, R2, R3 and R4, which may be identical or different, denote an alkyl or alkylcycloalkyl radical, optionally substituted or interrupted; (ii) R3 and/or R4 denote(s) a group: R8[OC2H3R7]n [OCH2CHOH-CH2]p  in which 0&lt;/=n&lt;/=4 and p denotes 0 or 1; R8 denotes H or an alkyl, alkenyl, alkylcycloalkyl or alkylaryl radical; (iii) R4 denotes an alkylphenyl radical; (iv), (v) R1 and R2 can form a saturated or unsaturated aromatic or non-aromatic heterocycle; (vi) R1, R2 and R3 form polycyclic derivatives with the nitrogen atoms; R5 denotes a group corresponding to the formula:  &lt;IMAGE&gt;   in which n is an integer varying between 0 and 10.

The present invention relates to new lipophilic salicylates containingat least one quaternary ammonium group, the process for preparing themand the pharmaceutical and cosmetic compositions containing them.

The use of various hexadecyltrimethylammonium salts, including thesalicylate, as a germicidal agent has been described in the prior art.See in particular SHELTON et al., J.A.C.S. (1946), 68, 753 as well asGAUTIER et al., Bull. Soc. Chim. France (1955), 634 and Broh-Kahn,Intern. Rec. Med. (1960), 173, 219.

The Applicant has just discovered, and this forms the subject of theinvention, new lipophilic quaternary ammonium salicylates.

It has found, in particular, that these compounds were especially activeas bactericidal and keratolytic agents in the treatment of infectious ornon-infectious dermatoses which are possibly of bacterial or fungalorigin and/or linked to the implantation of certain yeasts having apathogenic nature. In particular, these new compounds have the advantageof being able to be used in the treatment of acne, comedones andpsoriasis, and of preventing skin infections whose onset is a phenomenonsecondary to a cutaneous stress of some kind, such as cuts, burns, solarerythema or various kinds of inflammation. In addition, they have goodantidandruff and deodorant properties.

The Applicant has also discovered that certain compounds possess goodproperties of absorption of light and UV radiation.

In addition, these compounds can be used advantageously in ophthalmologyand for the treatment of buccal infections and inflammations of thenasal mucosae, and more generally for the treatment of viral conditions.These compounds possess, moreover, spermicidal properties.

These compounds possess, moreover, good preservative properties. Some ofthese compounds can be used on account of their surfactant andfoam-stabilizing properties.

The Applicant has discovered, in particular, that these new compoundspossessed special value in the treatment of acne.

As is well known, acne is a polymorphic skin disorder occurring atpuberty and regressing spontaneously in the large majority of cases atabout 20 to 25 years of age. In the individuals concerned, acne affectsall the areas rich in sebaceous glands (the forehead, the face, wings ofthe nose, trunk, back) with the exception of the scalp.

Although poorly defined, the etiopathogenesis of acne owes its origin tothe formation of a characteristic lesion, the comedo. The latter resultsfrom the obstruction of the pilosebaceous duct as a consequence of adyskeratinization of the region of the infundibilum of the duct.

The major effect of this obstruction is to modify the rheologicalproperties of the sebum and the physicochemical characteristics of themedium, such as pH, oxygen tension, and the like.

This modification permits the hyperproliferation of the residentcutaneous strains, chiefly Propionibacterium acnes, which is ananaerobic or air-tolerant strain.

The consequence of the bacterial hyperproliferation is to release intothe medium certain proteases or hyaluronidases of bacterial origin,which cause a lysis of the follicular sac and hence the release ofinflammatory compounds within the dermis, and initiate the body'sinflammatory type reaction.

While the nature of the inflammatory compounds has not at present beendetermined, their bacterial origin seems to be in little doubt,accounting for the good therapeutic success of antibacterial compounds,both orally and topically, in inflammatory acne.

For this purpose, antibacterial agents such as antibiotics, for exampleerythromycin, tetracycline and clindamycin have been recommended veryfrequently in the treatment of acne. These compounds give excellentresults, but their over-zealous use renders the Propionibacterium acnesstrains resistant to these same antibiotics, so that repeated treatmentmay prove to have little effect.

The Applicant has discovered that the new lipophilic quaternary ammoniumsalicylates had an anti-bacterial activity in vitro, with respect toPropionibacterium acnes, similar to that of the antibiotics usedpreviously, without, however, inducing phenomena of bacterialresistance.

The new lipophilic quaternary ammonium salicylates are especially moreactive towards Propionibacterium acnes strains thanhexadecyltrimethylammonium salicylate, as well as other quaternaryammonium derivatives having an organic counter-anion that are known inthe prior art.

The lipophilic quaternary ammonium salicylates according to theinvention also have the advantage of not being very irritant to theskin. These new compounds are, moreover, more capable of penetrating thestratum corneum in the case of a topical application.

The subject of the invention is hence, by way of new compounds,lipophilic quaternary salicylates defined below.

Another subject of the invention consists of therapeutic treatmentcompositions containing the compounds defined above.

The subject of the invention is also a composition and a process forcosmetic treatment based on these compounds.

Other subjects of the invention will emerge on reading the descriptionand examples which follow.

The lipophilic quaternary ammonium salicylates which constitute the mainsubject of the invention are compounds essentially corresponding to theformula: ##STR3## in which: (i) R₁, R₂, R₃ and R₄, which may beidentical or different, denote a C₁ to C₂₂ saturated or unsaturatedalkyl or alkylcycloalkyl radical which can optionally be interrupted byone or more groups chosen from ether, thioether, sulphoxide, ester,amide, sulphonamide, carbamate or ureido groups and/or which can bear,at the end of the chain or in the chain, one or more hydroxyl or halogengroup(s);

(ii) R₃ and/or R₄ denote(s) a group:

    R.sub.8 [OC.sub.2 H.sub.3 R.sub.7 ].sub.n [OCH.sub.2 CHOH--CH.sub.2 ].sub.p

in which: 0≦n≦4 and p denotes 0 or 1.

R₈ denotes H or a C₁ to C₁₈ alkyl, alkenyl, alkylcycloalkyl or alkylarylradical, it being possible for the alkyl groups to be linear or branchedand for the aliphatic or aromatic rings optionally to bear one or moreC₁ to C₄ alkyl or alkoxy substituent(s);

R₇ denotes H, CH₃ or CH₂ OH.

When R₇ denotes CH₂ OH, R₈ is then other than H and p equals 1.

In the other cases, p=0.

The group (OC₂ H₃ R₇) can denote either or both of the followingarrangements: ##STR4## R₁ and R₂ have the meanings assigned in paragraph(i); (iii) R₄ denotes the group; ##STR5## in which n denotes 0 or 1, inwhich case R₁, R₂ and R₃ have the meanings stated above, R₆ denotes ahydrogen, a hydroxyl, a halogen, an alkyl or hydroxyalkyl residue or aC₁ to C₁₈ acyl residue;

(iv) R₁ and R₂ form an aromatic heterocycle (in which case R₃ isnon-existent) corresponding to the formula: ##STR6## in which R₄ has themeanings stated above; (v) R₁ and R₂ form a saturated or unsaturatednon-aromatic heterocycle, optionally interrupted by an oxygen atom or anitrogen atom or a sulphur atom; in which case

R₄ denotes a group defined above and R₃ denotes a group also defined in(i);

(vi) R₁, R₂ and R₃ form, together with one or more nitrogen atoms,polycyclic derivatives such as diazabicyclooctane orhexamethylenetetramine, R₄ in this case denoting a group defined aboveunder (i) and (iii).

Generally speaking, the ammonium groups are such that at most two of theradicals R₁ to R₄ consist of 12 or more than 12 consecutive carbonatoms.

In the different cases mentioned above, R₅ denotes a group: ##STR7## nvarying from 0 to 10 inclusive.

The compounds according to the invention are preferably prepared from asalt such as, more especially, the corresponding quaternary ammoniumcarbonate, solubilized in alcoholic medium and preferably in methanol,to which is added the chosen lipophilic salicyclic acid derivative, alsosolubilized in an alcohol such as ethanol or methanol or alternativelyin an ether such as tetrahydrofuran. The reaction starts by itself andis followed by the evolution of carbon dioxide.

Preferred compounds are chosen, in particular, from the followingcompounds: hexadecyltrimethylammonium 5-octanoylsalicylate,hexadecyltrimethylammonium 5-decanoylsalicylate,hexadecyltrimethylammonium 5-dodecanoylsalicylate, hexadecylpyridinium5-octanoylsalicylate, hexadecylpyridinium 5-decanoylsalicylate,hexadecylpyridinium 5-dodecanoylsalicylate,benzyldimethylhexadecylammonium 5-octanoylsalicylate,benzyldimethylhexadecylammonium 5-decanoylsalicylate,benzyldimethylhexadecylammonium 5-dodecanoylsalicylate,benzyltrimethylammonium 5-decanoylsalicylate,hexadecyldimethyl(hydroxyethyl)ammonium 5-decanoylsalicylate,tetramethylammonium 5-dodecanoylsalicylate, dodecylethyldimethylammonium5-decanoylsalicylate, trimethyl-(β-hydroxyethyl)-ammonium5-decanoylsalicylate, trimethyl-(β-hydroxyethyl)-ammonium5-dodecanoylsalicylate, N-hexadecyl-N-methylimidazolinium5-dodecanoylsalicylate, N-dodecyl-N-methylmorpholinium5-decanoylsalicylate, N-methyl-N-octylpiperidinium5-dodecanoylsalicylate, 1'-azonia-4'-azabicyclo[2.2.2]octylhexadecane5-dodecanoylsalicylate, benzethonium 5-octanoylsalicylate, benzethonium5-dodecanoylsalicylate, N-(3-chloroallyl)hexaminium 5-octanoylsalicylateand N-(3-chloroallyl)hexaminium 5-dodecanoylsalicylate.

The pharmaceutical compositions which are the subject of the inventionare essentially characterized in that they are topical compositionscontaining at least one of the compounds corresponding to the formula(I) above in a pharmaceutically acceptable medium that is suitable fortopical application.

These compositions are especially suitable for the treatment of variousdermatoses such as acne.

The compositions can take the form of an aqueous or anhydrous solutionor dispersion, or alternatively the form of an emulsion or suspension,containing at least one compound corresponding to the formula (I) inconcentrations between 0.001 and 15% by weight based on the total weightof the composition, and preferably between 0.05 and 5%.

These compositions can contain pharmaceutically acceptable vehicles andadjuvants which are well known in the prior art. It is possible, forexample, to prepare solutions using one or more organic solvent(s) thatis/are acceptable from the physiological standpoint, chosen, in additionto water, from solvents such as acetone, ethanol, isopropyl alcohol,glycol ethers such as the products sold under the name "Dowanol",polyglycols and polyethylene glycols, C₁ -C₄ alkyl esters of short-chainacids, preferably ethyl or isopropyl lactate, fatty acid triglyceridessuch as the products marketed under the name "Miglyol", isopropylmyristate, animal, mineral and vegetable oils and polysiloxanes.

The compositions according to the invention can also contain thickeningagents such as cellulose and/or cellulose derivatives, in the proportionof 0.5 to 20% by weight based on the total weight of the composition.They can also contain gums such as xanthan, guar or carob gum or gumarabic, or alternatively polyethylene glycols, bentones andmontmorillonites, and the like.

These compositions according to the invention can also contain, incombination, antiacne agents such as retinoic derivatives, antibacterialagents, anti-inflammatories, and steroids having a non-hormonal action,in particular pregnenolone, which is already known for the treatment andcare of the skin, whose properties are described in U.S. Pat. No.2,791,534.

It is possible to add, if necessary, an adjuvant chosen fromantioxidants, surfactants, other preservatives, film-forming,keratolytic or comedolytic agents, perfumes and colourings.

For example, among antioxidants, t-butylhydroquinone, butylatedhydroxyanisole, butylated hydroxytoluene and α-tocopherol and itsderivatives may be mentioned.

The galenical forms chiefly conditioned for topical application take theform of creams, milks, gels, dispersions or microemulsions, lotionsthickened to a greater or lesser extent, impregnated pads, ointments orsticks, or alternatively the form of aerosol formulations in spray orfoam form or alternatively in the form of a cake of soap.

A subject of the invention resides in the use of the compounds of theformula I for the preparation of such compositions intended for thetreatment of dermatoses.

The compositions according to the invention can also be used for thecosmetic treatment of the skin, in particular as comedolytic,keratolytic, antisun or verrulytic agents, or as agents for treating thehair or scalp.

These compositions can assume forms similar to those mentioned above,and can contain adjuvants customarily used in cosmetics in compositionsintended for the care and cosmetic treatment of the skin.

The process for cosmetic treatment consists in applying such acomposition on the skin.

The antibacterial activity of the compounds according to the inventionwas studied by the dilution method in order to determine the MinimalInhibitory Concentration (MIC) according to the method described andemployed by G. A. DENYS et al., Antimicrobial Agents and Chemotherapy(1983) 23, 335-337, and J. J. LEYDEN et al., J. Am. Acad. Dermatol.(1983) 8 (1) 41-5, using Propionibacterium acnes strain ATCC 6919 as thestrain.

The minimal inhibitory concentrations (MIC), expressed in μg/ml (DMSO),of the lipophilic quaternary ammonium salicylates according to theinvention are shown in Table 1.

                                      TABLE I    __________________________________________________________________________    MIC Tests                    on                    ATCC 6919                    MIC    No      Name of the compound                    (μg/ml)                          R.sub.1                              R.sub.2                                     R.sub.3     R.sub.4   R.sub.5    __________________________________________________________________________     1      N-Hexadecyl-N,N,N-tri-                    21    CH.sub.3                              CH.sub.3                                     CH.sub.3    n-C.sub.16 H.sub.33                                                           H      methylammonium salicylate*     2      Hexadecyltrimethylammoni-                    26                                     **      um laurate*     3      Hexadecyltrimethylammoni-                    25                                     **      um stearate*     4      Hexadecyltrimethylammo-                    8     CH.sub.3                              CH.sub.3                                     CH.sub.3    n-C.sub.16 H.sub.33                                                           CO-nC.sub.7                                                           H.sub.15      nium 5-octanoylsalicylate     5      Hexadecyltrimethylammo-                    2.3   CH.sub.3                              CH.sub.3                                     CH.sub.3    n-C.sub.16 H.sub.33                                                           CO-nC.sub.9                                                           H.sub.19      nium 5-decanoylsalicylate     6      Hexadecyltrimethylammo-                    3.2   CH.sub.3                              CH.sub.3                                     CH.sub.3    n-C.sub.16 H.sub.33                                                           CO-nC.sub.11                                                           H.sub.23      nium 5-dodecanoylsalicylate     7      Hexadecylpyridinium 5- octanoylsalicylate                    2.4                               ##STR8##          n-C.sub.16 H.sub.33                                                           CO-nC.sub.7                                                           H.sub.15     8      Hexadecylpyridinium 5- decanoylsalicylate                    1.2                               ##STR9##          n-C.sub.16 H.sub.33                                                           CO-nC.sub.9                                                           H.sub.19     9      Hexadecylpyridinium 5- dodecanoylsalicylate                    1.2                               ##STR10##         n-C.sub.16 H.sub.33                                                           CO-nC.sub.11                                                           H.sub.23    10      Benzyldimethylhexadecyl- ammonium 5-octanoylsali- cylate                    0.54  CH.sub.3                              CH.sub.3                                     n-C.sub.16 H.sub.33                                                  ##STR11##                                                           CO-nC.sub.7                                                           H.sub.15    11      Benzyldimethylhexadecyl- ammonium 5-decanoylsali- cylate                    1.5   CH.sub.3                              CH.sub.3                                     n-C.sub.16 H.sub.33                                                  ##STR12##                                                           CO-nC.sub.9                                                           H.sub.19    12      Benzyldimethylhexa- decylammonium 5- dodecanoylsalicylate                    1     CH.sub.3                              CH.sub.3                                     n-C.sub.16 H.sub.33                                                  ##STR13##                                                           CO-nC.sub.11                                                           H.sub.23    13      Benzyltrimethylammo- nium 5-decanoylsali- cylate                    3.2   CH.sub.3                              CH.sub.3                                     CH.sub.3                                                  ##STR14##                                                           CO-nC.sub.9                                                           H.sub.19    14      Hexadecyldimethyl-                    3.6   CH.sub.3                              CH.sub.3                                     CH.sub.2 CH.sub.2 OH                                                 n-C.sub.16 H.sub.33                                                           CO-nC.sub.9                                                           H.sub.19      (hydroxyethyl)ammo-      nium 5-decanoylsali-      cylate    15      Tetramethylammonium                    2.5   CH.sub.3                              CH.sub.3                                     CH.sub.3    CH.sub.3  CO-nC.sub.11                                                           H.sub.23      5-dodecanoylsalicy-      late    16      Dodecylethyldimethyl-                    6.2   CH.sub.3                              CH.sub.3                                     C.sub.2 H.sub.5                                                 n-C.sub.12 H.sub.25                                                           CO-nC.sub.9                                                           H.sub.19      ammonium 5-decanoyl-      salicylate    17      Trimethyl-(β-hydroxy-                    11    CH.sub.3                              CH.sub.3                                     CH.sub.3    C.sub.2 H.sub.4 OH                                                           CO-nC.sub.9                                                           H.sub.19      ethyl)ammonium 5-      decanoylsalicylate    18      Trimethyl-(β-hydroxy-                    4.8   CH.sub.3                              CH.sub.3                                     CH.sub.3    C.sub.2 H.sub.4 OH                                                           CO-nC.sub.11                                                           H.sub.23      ethyl)ammonium 5-      dodecanoylsalicylate    19      N-(2-Hydroxyethyl)-                    >100  CH.sub.3                              CH.sub.3                                     CH.sub.3    CH.sub.2 CH.sub.2 OH                                                           H      N,N,N-trimethylammo-      nium salicylate*    20      N-Hexadecyl-N-methyl- imidazolinium 5- dodecanoylsalicylate                    13.5                           ##STR15##             n-C.sub.16 H.sub.33                                                           CO-nC.sub.11                                                           H.sub.23    21      N-Dodecyl-N-methyl- morpholinium 5- decanoylsalicylate                    9                           ##STR16## CH.sub.3    n-C.sub.12 H.sub.25                                                           CO-nC.sub.9                                                           H.sub.19    22      N-Methyl-N-octylpiper- idinium 5-dodecan- oylsalicylate                    4.9                           ##STR17## CH.sub.3    n-C.sub.8 H.sub.17                                                           CO-nC.sub.11                                                           H.sub.23    23      1' -Azonia-4'-azabi- cyclo[ 2.2.2]octyl- hexadecane 5-dodecan- oylsalicy      late          1.5                           ##STR18##             n-C.sub.16 H.sub.33                                                           CO-nC.sub.11                                                           H.sub.23    24      Benzethonium 5- octanoylsalicylate                    1.2   CH.sub.3                              CH.sub.3                                     C.sub.8 H.sub.17 -φ-(OCH.sub.2                                     CH.sub.2).sub.2                                                  ##STR19##                                                           CO-nC.sub.7                                                           H.sub.15    25      Benzethonium 5- dodecanoylsalicylate                    2     CH.sub.3                              CH.sub.3                                     C.sub.8 H.sub.17 -φ-(OCH.sub.2                                     CH.sub.2).sub.2                                                  ##STR20##                                                           CO-nC.sub.11                                                           H.sub.23    __________________________________________________________________________     *Controls     **Not corresponding to the formula I

It emerges from this table that the lipophilic salicylates according tothe invention are markedly more active with respect to thePropionibacterium acnes strain than the salicylates previouslyrecommended in the prior art.

The examples which follow are designed to illustrate on the one hand theprocesses for the preparation of the compounds according to theinvention, and on the other hand pharmaceutical and cosmeticcompositions employing these compounds.

PREPARATION EXAMPLE 1

Preparation of N-hexadecyl-N,N,N-trimethylammonium 5-octanoylsalicylate:compound no. 4 (Table I).

2 g (7.57 mmol) of 5-octanoylsalicylic acid, dissolved beforehand in 15ml of methanol, are added to a solution of 2.62 g (4.16 mmol) ofhexadecyltrimethylammonium carbonate dissolved in 15 ml of methanol; themixture is stirred for 1 hour at room temperature and the solvent isthen evaporated off, and the white solid residue obtained isrecrystallized in an acetone/diethyl ether mixture to give 3.8 g (91.5%yield) of hexadecyltrimethylammonium 5-octanoylsalicylate.

M.p. 130° C. (acetone/diethyl ether) Elementary analysis: C₃₄ H₆₁ NO₄ ;M=547.9

    ______________________________________              C          H      N    ______________________________________    Calculated %                74.54        11.22  2.56    Found %     74.48        11.31  2.62    ______________________________________

The ¹ H and ¹³ C NMR spectra confirm the expected structure with thecharacteristic values for the ammonium cation and the5-octanoylsalicylate anion.

PREPARATION EXAMPLE 2

Preparation of N-hexadecyl-N,N,N-trimethylammonium 5-decanoylsalicylate:compound no. 5.

2 g (6.85 mmol) of 5-decanoylsalicylic acid, dissolved beforehand in 15ml of ethanol, are added to a solution of 2.2 g (3.5 mmol) ofhexadecyltrimethylammonium carbonate dissolved in 15 ml of methanol; themixture is stirred for 1 hour at room temperature, the solvents are thenevaporated off and the white solid residue obtained is recrystallized inan acetone/diethyl ether mixture to give 3.8 g (96% yield) ofhexadecyltrimethylammonium 5-decanoylsalicylate.

M.p. 130° C. (acetone/diethyl ether) Elementary analysis: C₃₆ H₆₅ NO₄ ;M=575.9

    ______________________________________              C          H      N    ______________________________________    Calculated %                75.08        11.37  2.43    Found %     75.05        11.42  2.44    ______________________________________

The ¹ H and ¹³ C NMR spectra confirm the expected structure with thecharacteristic values for the quaternary ammonium cation and the5-decanoylsalicylate anion.

PREPARATION EXAMPLE 3

Preparation of N-hexadecyl-N,N,N-trimethylammonium5-dodecanoylsalicylate: compound no. 6.

2 g (6.25 mmol) of 5-dodecanoylsalicylic acid, dissolved beforehand in15 ml of ethanol, are added to a solution of 2 g (3.18 mmol) ofhexadecyltrimethylammonium carbonate dissolved in 15 ml of methanol; themixture is stirred for 1 hour at room temperature, the solvents are thenevaporated off and the white solid residue obtained is recrystallized inan acetone/diethyl ether mixture to give 3.5 g (93% yield) ofhexadecyltrimethylammonium 5-dodecanoylsalicylate.

M.p. 130° C. (acetone/diethyl ether) Elementary analysis: C₃₈ H₆₉ NO₄ ;M=604

    ______________________________________              C          H      N    ______________________________________    Calculated %                75.57        11.52  2.32    Found %     75.17        11.61  2.5    ______________________________________

The ¹³ C NMR spectrum confirms the expected structure with thecharacteristic values for the quaternary ammonium cation and the5-dodecanoylsalicylate anion.

The UV spectrum (ethanol) shows an absorption λ_(max) =280 nm; the molarextinction coefficient ε=14080.

PREPARATION EXAMPLE 4

Preparation of N-hexadecylpyridinium 5-octanoylsalicylate monohydrate:compound no. 7.

2 g (7.57 mmol) of 5-octanoylsalicylic acid, dissolved beforehand in 15ml of methanol, are added to a solution of 2.5 g (3.79 mmol) ofhexadecylpyridinium carbonate dissolved in 15 ml of methanol; themixture is stirred for 1 hour at room temperature, the brown cruderesidue obtained is then filtered off and the filtrate is evaporated todryness to give 4.2 g (98% yield) of hexadecylpyridinium5-octanoylsalicylate.

Elementary analysis: C₃₆ H₅₇ NO₄.1H₂ O; M=585.9

    ______________________________________              C          H      N    ______________________________________    Calculated %                73.8         10.15  2.39    Found %     73.22         9.77  2.31    ______________________________________

The ¹³ C NMR spectrum confirms the expected structure with thecharacteristic values for the quaternary ammonium cation and the5-octanoylsalicylate anion.

The UV spectrum (ethanol) shows an absorption λ_(max) =279 nm; the molarextinction coefficient ε=21450.

PREPARATION EXAMPLE 5

Preparation of N-hexadecylpyridinium 5-decanoylsalicylate sesquihydrate;compound no. 8.

2 g (6.85 mmol) of 5-decanoylsalicylic acid, dissolved beforehand in 15ml of ethanol, are added to a solution of 2.3 g (3.44 mmol) ofhexadecylpyridinium carbonate dissolved in 15 ml of methanol; themixture is stirred for 1 hour at room temperature, the solvents are thenevaporated off and the brown residue obtained is recrystallized in anacetone/diethyl ether mixture to give 3.9 g (96% yield) ofhexadecylpyridinium 5-decanoylsalicylate.

M.p. 73° C. (acetone/diethyl ether) Elementary analysis: C₃₈ H₆₁NO₄.1.5H₂ O; M=622.9

    ______________________________________              C          H      N    ______________________________________    Calculated %                73.27        10.36  2.25    Found %     73.64         9.64  1.82    ______________________________________

The ¹³ C NMR spectrum confirms the expected structure with thecharacteristic values for the aromatic quaternary ammonium cation and5-decanoylsalicylate.

PREPARATION EXAMPLE 6

Preparation of N-hexadecylpyridinium 5-dodecanoylsalicylate hydrate:compound no. 9.

2 g (6.25 mmol) of 5-dodecanoylsalicylic acid, dissolved beforehand in15 ml of ethanol, are added to a solution of 2.1 g (3.14 mmol) ofhexadecylpyridinium carbonate dissolved in 15 ml of methanol; themixture is stirred for 1 hour at room temperature, the solvents are thenevaporated off and the brown residue obtained is recrystallized in anacetone/diethyl ether mixture to give 3.7 g (95% yield) ofhexadecylpyridinium 5-dodecanoylsalicylate.

M.p. 79° C. (acetone/diethyl ether) Elementary analysis: C₄₀ H₆₅ NO₄.1H₂O; M=642

    ______________________________________              C          H      N    ______________________________________    Calculated %                74.84        10.52  2.18    Found %     74.61        10.12  1.96    ______________________________________

The ¹³ C NMR spectrum confirms the expected structure with thecharacteristic values for the aromatic quaternary ammonium cation and5-dodecanoylsalicylate.

The UV spectrum (ethanol) shows an absorption λ_(max) =279 nm; the molarextinction coefficient ε=18910.

PREPARATION EXAMPLE 7

Preparation of N-benzyl-N,N-dimethyl-N-hexadecylammonium5-octanoylsalicylate: compound no. 10.

2 g (7.57 mmol) of 5-octanoylsalicylic acid, dissolved beforehand in 15ml of methanol, are added to a solution of 3 g (3.84 mmol) ofbenzyldimethylhexadecylammonium carbonate dissolved in 15 ml ofmethanol; the mixture is stirred for 1 hour at room temperature, thesolvent is then evaporated off and the white residue is recrystallizedin an acetone/diethyl ether mixture to give 4.5 g (95% yield) ofbenzyldimethylhexadecylammonium 5-octanoylsalicylate.

M.p. 114° C. (acetone/diethyl ether) Elementary analysis: C₄₀ H₆₅ NO₄ ;M=623.9

    ______________________________________              C          H      N    ______________________________________    Calculated %                77.00        10.50  2.24    Found %     77.02        10.58  2.38    ______________________________________

The ¹³ C NMR spectrum confirms the expected structure with thecharacteristic signals of the quaternary ammonium cation and5-octanoylsalicylate.

The compounds of Examples nos. 8 to 21 are prepared in a manner similarto that described in Examples 1 to 7.

PREPARATION EXAMPLE 8

Preparation of N-benzyl-N,N-dimethyl-N-hexadecylammonium5-decanoylsalicylate: compound no. 11.

M.p. 113° C. (acetone/diethyl ether) Elementary analysis: C₄₂ H₆₉ NO₄ ;M=652

    ______________________________________              C          H      N    ______________________________________    Calculated %                77.37        10.67  2.15    Found %     77.22        10.69  2.25    ______________________________________

PREPARATION EXAMPLE 9

Preparation of N-benzyl-N,N-dimethyl-N-hexadecylammonium5-dodecanoylsalicylate: compound no. 12.

M.p. 117° C. (acetone/diethyl ether) Elementary analysis: C₄₄ H₇₃ NO₄ ;M=680.08

    ______________________________________              C          H      N    ______________________________________    Calculated %                77.71        10.82  2.06    Found %     77.15        10.81  2.08    ______________________________________

The UV spectrum (ethanol) shows an absorption λ_(max) =281 nm; the molarextinction coefficient ε=17720.

PREPARATION EXAMPLE 10

Preparation of N-benzyl-N,N,N-trimethylammonium 5-decanoylsalicylate:compound no. 13.

M.p. 135° C. (acetone/diethyl ether) Elementary analysis: C₂₇ H₃₉ NO₄ ;M=441.6

    ______________________________________              C          H      N    ______________________________________    Calculated %                73.43        8.9    3.17    Found %     73.01        8.74   3.18    ______________________________________

PREPARATION EXAMPLE 11

Preparation of N-hexadecyl-N,N-dimethyl-N-(β-hydroxyethyl)ammonium5-decanoylsalicylate: compound no. 14.

Elementary analysis: C₃₇ H₆₈ NO₅.1/2H₂ O; M=615.96

    ______________________________________              C          H      N    ______________________________________    Calculated %                72.15        11.29  2.12    Found %     72.51        10.85  2.27    ______________________________________

PREPARATION EXAMPLE 12

Preparation of N,N,N,N-tetramethylammonium 5-dodecanoylsalicylate:compound no. 15.

M.p. 97° C. (acetone/diethyl ether) Elementary analysis: C₂₃ H₄₀ NO₄ :M=390.15

    ______________________________________              C          H      N    ______________________________________    Calculated %                70.8         10.33  3.59    Found %     70.27         9.87  3.38    ______________________________________

PREPARATION EXAMPLE 13

Preparation of trimethyl-(β-hydroxyethyl)ammonium5-dodecanoylsalicylate: compound no. 18.

M.p. 67° C. (methanol/diethyl ether) Elementary analysis: C₂₄ H₄₁ NO₅ :M=423.6

    ______________________________________              C          H      N    ______________________________________    Calculated %                68.05        9.76   3.31    Found %     68.09        9.59   2.69    ______________________________________

UV spectrum (ethanol): λ_(max) =280 nm; ε=16640.

PREPARATION EXAMPLE 14

Preparation of trimethyl-(β-hydroxyethyl)ammonium 5-decanoylsalicylate:compound no. 17.

Elementary analysis: C₂₂ H₃₅ NO₅.3/4H₂ O: M=407.6

    ______________________________________              C          H      N    ______________________________________    Calculated %                64.82        9.51   3.43    Found %     64.75        9.36   3.01    ______________________________________

PREPARATION EXAMPLE 15

Preparation of dimethylethyldodecylammonium 5-decanoylsalicylate:compound no. 16.

M.p. 65° C. (acetone/diethyl ether) Elementary analysis: C₃₃ H₅₉ NO₄.H₂O; M=551.9

    ______________________________________              C          H      N    ______________________________________    Calculated %                71.8         11.14  2.62    Found %     72.07        10.74  2.33    ______________________________________

PREPARATION EXAMPLE 16

Preparation of N-hexadecyl-N-methylimidazolinium 5-dodecanoylsalicylate:compound no. 20.

M.p. 82° C. (acetone/diethyl ether) Elementary analysis: C₃₉ H₆₆ N₂O₄.1.5H₂ O; M=654

    ______________________________________              C          H      N    ______________________________________    Calculated %                71.62        10.62  4.28    Found %     71.82        10.68  4.02    ______________________________________

UV spectrum (ethanol): λ_(max) =281 nm; ε=15385

PREPARATION EXAMPLE 17

Preparation of 1'-azonia-4'-azabicyclo[2.2.2]octylhexadecane5-dodecanoylsalicylate: compound no. 23.

M.p. 96° C. (acetone/diethyl ether) Elementary analysis: C₄₁ H₇₂ N₂O₄.H₂ O; M=675

    ______________________________________              C          H      N    ______________________________________    Calculated %                72.95        11.04  4.15    Found %     72.57        10.93  4.3    ______________________________________

PREPARATION EXAMPLE 18

Preparation of N-methyl-N-octylpiperidinium 5-dodecanoylsalicylate:compound no. 22.

M.p. 45° C. (acetone/diethyl ether) Elementary analysis: C₃₃ H₅₇NO₄.0.5H₂ O; M=540.9

    ______________________________________              C          H      N    ______________________________________    Calculated %                73.28        10.81  2.59    Found %     73.31        11.02  2.7    ______________________________________

PREPARATION EXAMPLE 19

Preparation of N-dodecyl-N-methylmorpholinium 5-decanoylsalicylate:compound no. 21.

M.p. 78° C. (acetone/diethyl ether) Elementary analysis: C₃₄ H₅₉ NO₅ ;M=561.8

    ______________________________________              C          H      N    ______________________________________    Calculated %                72.68        10.58  2.49    Found %     72.58        10.68  2.6    ______________________________________

PREPARATION EXAMPLE 20

Preparation of benzethonium 5-octanoylsalicylate.

2.2 g (8.4 mmol) of 5-octanoylsalicylic acid, dissolved beforehand in100 ml of methanol, are added to a solution of 3.7 g (4.2 mmol) ofbenzethonium carbonate dissolved in 100 ml of methanol; the mixture isstirred for 1 hour at room temperature, the solution is then filteredand the filtrate is evaporated to dryness to give 5.5 g (98% yield) ofbenzethonium 5-octanoylsalicylate.

Elementary analysis: C₄₂ H₆₁ NO₆.2H₂ O; MW=712

    ______________________________________              C          H      N    ______________________________________    Calculated %                70.85        9.20   1.97    Found %     70.93        9.07   2.07    ______________________________________

The ¹³ C NMR spectrum confirms the expected structure with thecharacteristic values for the quaternary ammonium cation and theoctanoylsalicylate anion.

PREPARATION EXAMPLE 21

Preparation of benzethonium 5-dodecanoylsalicylate.

2 g (6.4 mmol) of 5-dodecanoylsalicylic acid, dissolved beforehand in100 ml of ethanol, are added to a solution of 2.82 g (3.2 mmol) ofbenzethonium carbonate dissolved in 100 ml of methanol; the mixture isstirred for 1 hour at room temperature, the solution is then filteredand the filtrate is evaporated to dryness to give 4.5 g (97% yield) ofbenzethonium 5-dodecanoylsalicylate.

Elementary analysis: C₄₆ H₆₉ NO₆.H₂ O; MW=750

    ______________________________________              C          H      N    ______________________________________    Calculated %                73.66        9.54   1.87    Found %     73.60        9.48   1.85    ______________________________________

The ¹³ C NMR spectrum confirms the expected structure with thecharacteristic values for the quaternary ammonium cation and the5-dodecanoylsalicylate anion.

The term benzethonium denotes:N,N-dimethyl-N-[2-{2-[4-(1,1,3,3-tetramethylbutyl)phenoxy]-ethoxy}ethyl]benzenemethaminium,orbenzyldimethyl-[2-{2-[p-(1,1,3,3-tetramethylbutyl)phenoxy]-ethoxy}ethyl]ammonium.

The examples which follow are designed to illustrate more especiallypharmaceutical or cosmetic compositions employing the compoundsaccording to the invention.

Pharmaceutical and cosmetic compositions EXAMPLE 1

The following composition is prepared:

    ______________________________________    Hydroxypropylcellulose    1.5     g    Hexadecyltrimethylammonium 5-decanoyl-                              3.0     g    salicylate    Isopropanol               qs 100  g    ______________________________________

EXAMPLE 2

The following composition is prepared:

    ______________________________________    Hydroxypropylcellulose    1.5     g    Ethyl lactate             15.0    g    Hexadecyltrimethylammonium 5-dodecanoyl-                              2.0     g    salicylate    Isopropanol               qs 100  g    ______________________________________

EXAMPLE 3

The following composition is prepared:

    ______________________________________    Hydroxypropylcellulose   1.0     g    Butylated hydroxytoluene 0.02    g    Benzyltrimethylammonium 5-decanoyl-                             0.5     g    salicylate    Ethanol                  qs 100  g    ______________________________________

EXAMPLE 4

The following composition is prepared:

    ______________________________________    Hydroxypropylcellulose    1.5     g    Butylated hydroxytoluene  0.01    g    C.sub.8 -C.sub.12 fatty acid triglycerides                              10.0    g    Hexadecylpyridinium 5-dodecanoylsalicylate                              5.0     g    Isopropanol               qs 100  g    ______________________________________

The compositions of Examples 1 to 4 take the form of a gel, and areintended especially for the topical treatment of acne.

EXAMPLE 5

The following composition is prepared:

    ______________________________________    Isopropanol               46.0 g    Hexadecyltrimethylammonium 5-dodecanoyl-                               5.0 g    salicylate    C.sub.8 -C.sub.12 fatty acid triglycerides                              49.0 g    ______________________________________

EXAMPLE 6

The following composition is prepared:

    ______________________________________    Ethanol               69.0 g    Ethyl lactate         10.0 g    Hexadecylpyridinium 5-decanoyl-                           1.0 g    salicylate    C.sub.8 -C.sub.12 fatty acid triglycerides                          20.0 g    ______________________________________

EXAMPLE 7

The following composition is prepared:

    ______________________________________    Isopropanol             47.0 g    Acetone                 10.0 g    Ethyl lactate           10.0 g    Benzyltrimethylammonium 5-decanoyl-                             3.0 g    salicylate    C.sub.8 -C.sub.12 fatty acid triglycerides                            30.0 g    ______________________________________

EXAMPLE 8

The following composition is prepared:

    ______________________________________    Ethanol                   95.08  g    Butylated hydroxytoluene  0.02   g    Hexadecyltrimethylammonium 5-octanoyl-                              4.0    g    salicylate    ______________________________________

These compositions of Examples 5, 6, 7 and 8 take the form of a lotionwhich is particularly effective in the treatment of acne.

EXAMPLE 9

The following composition is prepared:

    ______________________________________    White vaseline            50.0 g    Liquid paraffin           15.0 g    Refined paraffin wax      32.0 g    Hexadecyltrimethylammonium 5-dodecanoyl-                               3.0 g    salicylate    ______________________________________

This composition takes the form of a stick which is suitable for thetreatment of acne.

EXAMPLE 10

    ______________________________________    White vaseline          50.0 g    Liquid paraffin         13.0 g    Refined paraffin wax    32.0 g    Trimethyl-(β-hydroxyethyl)ammonium                             5.0 g    5-dodecanoylsalicylate    ______________________________________

This composition takes the form of a stick which is suitable forprotecting the lips against solar radiation.

We claim:
 1. Lipophilic quaternary ammonium salicylate, corresponding tothe formula: ##STR21## in which (i) R₁, R₂, R₃ and R₄, which may beidentical or different, denote a C₁ to C₂₂ alkyl or alkylcycloalkylradical or a C₁ to C₂₂ alkyl or alkylcycloalkyl radical interrupted byone or more ether, thioether, sulphoxide, ester, amide, sulphonamide,carbamate or ureido groups or which bears, at the end of the chain or inthe chain, one or more hydroxyl or halogen group;(ii) R₃ or R₄ denote agroup: R₈ --OC₂ H₃ R₇)_(n) (OCH₂ CHOH--CH₂ --_(p) in which > n≦4 and pdenotes 0 or 1; R₈ denotes H or a C₁ to C₁₈ alkyl, alkenyl,alkylcycloalkyl or alkylaryl radical, it being possible for the alkylgroups to be linear or branched and for the aliphatic or aromatic ringsto bear one or more C₁ to C₄ alkyl or alkoxy substituent; R₇ denotes H,CH₃ or CH₂ OH; when R₇ denotes CH₂ OH, R₈ is then other than H and pequals in the other cases, p=0; the group (OC₂ H₃ R₇) can denote eitheror both of the following formulas: ##STR22## R₁ and R₂ have the meaningsrecited in paragraph (i); or (iii) R₄ denotes the group: ##STR23## inwhich n denotes 0 or 1; R₁, R₂ and R₃ having the same meanings as inparagraph (i); R₆ denotes a hydrogen, a hydroxyl, a halogen, an alkyl orhydroxyalkyl residue or a C₁ to C₁₈ acyl residue; and R₅ denotes a groupcorresponding to the formula: ##STR24## in which n is an integer varyingbetween 0 and
 10. 2. Lipophilic quaternary ammonium salicylate accordingto claim 1, wherein R₄ denotes a benzyl group and R₁, R₂ and R₃ have themeanings recited in paragraph (i).
 3. Lipophilic quaternary ammoniumsalicylate of claim 1, selected from the group consistingof:hexadecyltrimethylammonium 5-octanoylsalicylate,hexadecyltrimethylammonium 5-decanoylsalicylate,hexadecyltrimethylammonium 5-dodecanoylsalicylate,benzyldimethylhexadecylammonium 5-octanoylsalicylate,benzyldimethylhexadecylammonium 5-decanoylsalicylate,benzyldimethylhexadecylammonium 5-dodecanoylsalicylate,benzyltrimethylammonium 5-decanoylsalicylate,hexadecyldimethyl(hydroxyethyl)ammonium 5-decanoylsalicylate,tetramethylammonium 5-dodecanoylsalicylate, dodecylethyldimethylammonium5-decanoylsalicylate, trimethyl-(β-hydroxyethyl)ammonium5-decanoylsalicylate, trimethyl-(β-hydroxyethyl)ammonium5-dodecanoylsalicylate,-N-benzethonium 5-octanoylsalicylate,benzethonium 5-dodecanoylsalicylate, 5-octanoylsalicylate andN-(3-chloroallyl)hexaminium 5-dodecanoylsalicy.
 4. Topical compositionintended for the treatment of dermatoses or skin disorders containing ina pharmaceutically or cosmetically acceptable medium at least onelipophilic quaternary ammonium salicylate of formula (I): ##STR25## inwhich (i) R₁, R₂, R₃ and R₄, which may be identical or different, denotea C₁ to C₂₂ alkyl or alkylcycloalkyl radical or a C₁ to C₂₂ alkyl oralkylcycloalkyl radical interrupted by one or more ether, thioether,sulphoxide, ester, amide, sulphonamide, carbamate or ureido groups orwhich bears, at the end of the chain or in the chain, one or morehydroxyl or halogen group;(ii) R₃ or R₄ denote a group: R₈ --OC₂ H₃R₇)_(n) (OCH₂ CHOH--CH₂ --_(p) in which ≦ n≦4 and p denotes 0 or 1; R₈denotes H or a C₁ to C₁₈ alkyl, alkenyl, alkylcycloalkyl or alkylarylradical, it being possible for the alkyl groups to be linear or branchedand for the aliphatic or aromatic rings to bear one or more C₁ to C₄alkyl or alkoxy substituent; R₇ denotes H, CH₃ or CH₂ OH; when R₇denotes CH₂ OH, R₈ is then other than H and p equals 1; in the othercases, p=0; the group (OC₂ H₃ R₇) can denote either or both of thefollowing formulas: ##STR26## R₁ and R₂ have the meanings recited inparagraph (i); or (iii) R₄ denotes the group: ##STR27## in which ndenotes 0 or 1; R₁, R₂ and R₃ having the same meanings as in paragraph(i); R₆ denotes a hydrogen, a hydroxyl, a halogen, an alkyl orhydroxyalkyl residue or a C₁ to C₁₈ acyl residue; and R₅ denotes a groupcorresponding to the formula: ##STR28## in which n is an integer varyingbetween 0 and
 10. 5. Composition according to claim 4, containing incombination with the compound of formula (I), at least one otherantiacne agent selected from the group consisting of pregnenolone,retinoic derivatives, antibiotics and anti-inflammatories. 6.Composition according to claim 4 in the form of a solution, anhydrousdispersion, emulsion or suspension, containing the lipophilic quaternaryammonium salicylate of formula (I) at a concentration of between 0.001and 15% by weight based on the total weight of the composition.
 7. Amethod of treating acne comprising applying to the affected area of skina composition comprising an effective amount of at least one compound ofclaim 1 and a pharmaceutically acceptable carrier.
 8. A method oftreating dandruff comprising applying to the scalp a compositioncomprising at least one compound of claim 1 and a pharmaceuticallyacceptable carrier.
 9. A method of treating warts comprising applying toa wart a composition comprising an effective amount of at least onecompound of claim 1 and a pharmaceutically acceptable carrier.
 10. Amethod of treating solar erythema comprising applying to the affectedarea of skin a composition comprising an effective amount of at leastone compound of claim 1 and a pharmaceutically acceptable carrier.
 11. Amethod of treating inflammations of the skin comprising applying to theaffected area of skin a composition comprising an effective amount of atleast one compound of claim 1 and a pharmaceutically acceptable carrier.